Paediatric onset with : 1) autoimmunity, that is predominantly haematological, but any other autoimmunity can be displayed. 2) enlargement of the spleen and/or lymph nodes due to accumulation of polyclonal lymphocytes. 3) peripheral blood expansion of T cells expressing the TCRalpha/beta but not CD4 and CD8 (double-negative T cells). 4) decreased function of the Fas death receptor.

Neoplastic risk

increased risk of lymphomas

Treatment

vigorous immune suppression

Evolution

autoimmunity may remit in adulthood but lymphoproliferation generally persists. Increased risk of lymphomas in adulthood.

Prognosis

good on survival, but autoimmune haemolytic anaemia may be occasionally lethal.

Genes involved and Proteins

Note

The disease is due to inherited defects decreasing function of the Fas (CD95) death receptor, involved in switching off the immune response by triggering apoptosis of activated lymphocytes. The mutation mostly hits the Fas gene ( type-Ia), but rare mutations of the Fas ligand gene ( type-Ib) or the caspase-10 gene (ALPS-type-IIa) gene have also been described. Two siblings carrying a homozygous mutation of the caspase-8 gene displayed ALPS plus hypogammaglobulinemia and increased susceptibility to infections; this disease has been named caspase-8 deficiency, but some authors included it in ALPS as ALPS type-IIb. Caspase-8 and caspase-10 are involved in Fas signalling. Some authors used the term type-III to name the disease caused by unknown mutations hitting the Fas signalling pathway, others used it to name displayed by patients with normal Fas function. Rieux-Laucat described a subgroup of patients carrying somatic mutations of the Fas gene in a subset of peripheral lymphocytes (mosaic type-Ia or type-Iam). Since most patients with -Ia are heterozygous, the term type-0 has been used to name the rare and aggressive disease caused by homozygous mutations of the Fas gene. The genetic background may influence the disease onset. Variants of the gene of perforin can act as predisposition factors.

multiple loss-of-function mutations have been reported in . They may decrease Fas expression or cause expression of receptors with dominant negative activity on Fas function. Mutations in the death domain have the highest penetrance.

activated cytotoxic cells (CTL and NK) and TH1 cells, but also expressed in other tissues

Localisation

type II transmembrane protein

Function

triggers apoptosis of Fas-expressing cells

Mutations

Germinal

two patients with type-Ib have been described to date. One carried a 84-bp deletion in exon 4 causing a 28-aa in-frame deletion. The other carried a A247E substitution in exon 4. Both mutations decreased FasL function.

protein of 496 amino acids. Several isoforms deriving from alternative splicing have been described.

Expression

ubiquitous

Localisation

cytosolic

Function

cystein-aspartate protease (caspase) triggering apoptosis. It binds to the adapter molecule FADD that associates with the intracytoplasmic tail of death receptors such as Fas and triggers the extrinsic pathway of apoptosis.

Mutations

Germinal

homozygous R248W substitutions has been described in two siblings with plus immunodeficiency. The mutated protein lost the enzyme activity.

it is stored in the lytic granules and secreted against the target cell

Function

it polymerizes on the membrane of target cells and forms pores

Homology

high sequenze homology to the C9 complement component

Mutations

Germinal

several PRF1 mutations have been associated with HLH and lymphomas. These mutations can inhibit either expression or function of perforin. A heterozygous N252S amino acid substitution has been described in one patient with type-Ia (i.e. carrying also a heterozygous mutation of the Fas gene) and one patient with type-III (i.e. with defective Fas function caused by an unknown gene alteration). It has been suggested that the PRF1 mutation may cooperate with the mutation hitting the Fas system in inducing ALPS development.

Bibliography

Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.